Abstract：
Macrolide antibiotics, pivotal in clinical therapeutics, are confronting resistance challenges mediated by enzymes like macrolide esterases, which are classified into Ere-type and the less studied Est-type. In this study, we provide the biochemical confirmation of EstX, an Est-type macrolide esterase that initially identified as unknown protein in the 1980s. EstX is capable of hydrolyzing four 16-membered ring macrolides, encompassing both veterinary (tylosin, tidipirosin, and tilmicosin) and human-use (leucomycin A5) antibiotics. It uses typical catalytic triad (Asp233-His261-Ser102) from alpha/beta hydrolase superfamily for ester bond hydrolysis. Further genomic context analysis suggests that the dissemination of estX is likely facilitated by mobile genetic elements such as integrons and transposons. The global distribution study indicates that bacteria harboring the estX gene, predominantly pathogenic species like Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae, are prevalent in 74 countries across 6 continents. Additionally, the emergence timeline of the estX gene suggests its proliferation may be linked to the overuse of macrolide antibiotics. The widespread prevalence and dissemination of Est-type macrolide esterase highlight an urgent need for enhanced monitoring and in-depth research, underlining its significance as an escalating public health issue.
摘要：
大环内酯类抗生素,在临床治疗中至关重要，正面临由大环内酯酯酶等酶介导的抗性挑战，分为Ere型和研究较少的Est型。在这项研究中,我们提供EstX的生化确认，一种Est型大环内酯酯酶，最初在1980年代被鉴定为未知蛋白质。EstX能够水解四种16元环大环内酯，包括两种兽药(泰乐菌素，替地吡松,和替米考星）和人用（白霉素A5）抗生素。它使用来自α/β水解酶超家族的典型催化三联体(Asp233-His261-Ser102)进行酯键水解。进一步的基因组背景分析表明，estX的传播可能是由整合子和转座子等可移动的遗传元件促进的。全球分布研究表明，携带estX基因的细菌，主要致病物种如大肠杆菌，肠沙门氏菌,和肺炎克雷伯菌,流行于6大洲的74个国家。此外,estX基因的出现时间线提示其增殖可能与大环内酯类抗生素的过度使用有关.Est型大环内酯酯酶的广泛流行和传播凸显出迫切需要加强监测和深入研究,强调其作为一个不断升级的公共卫生问题的重要性。
